3-enol ethers of 2-hydroxymethyl-3-oxo-5alpha-steroids and process for preparing same



United States Patent 3 155 692 3-ENOL ETHERS or i-HSZDROXYMETHYL-Ii-OXO-SZ-lSII'IEIROIDS AND PROCESS FOR PREPARING S Bernard Ellis, Derek Burn,and Vladimir Petrow, London,

England, assignors to The British Drug Houses Limited No Drawing. FiledJan. 24, 1963, Ser. No. 253,751 Claims priority, application GreatBritain, Jan. 26, 1962,

3,001/62 11 Claims. (Cl. 260397.4)

This invention is for improvements in relating to organic compounds andhas particular reference to steroidal materials containing an additionalcarbon substituent at C It is an object of the present invention toprovide a new and general process for the preparation of the 3-enolethers of 2-hydroxymethyl-3-oxo-5a-steroids, and additionally to providesuch compounds for therapeutic, veterinary or investigational use or foremployment as intermediates. The steroidal products of our co-pendingapplication No. 253,750, filed January 24, 1963, which may be regardedstructurally as the 3-enol ethers of 2- formyl-3@xo-Sa-steroids, may beconverted by the process of this invention into the corresponding2-hydroxymethyl derivatives. Many of the herein described derivativespossess valuable biological properties which render them of value in,for example, the veterinary field. Thus, for example, the derivatives ofl7B-hydroxya-androstane herein described possess claudogenic propertiesincluding ovulation inhibiting properties. The derivatives of17a,2I-dihydroXy-Sa-pregnane-11,20-dione and its 21- and 17,21-esterslikewise show claudogenic activity. Progestational activity may be shownby derivatives of 17a-acyloxy-5a-pregnan-ZO-one In addition, the2-hydroxymethyl derivatives which fall within the scope of the presentinvention are valuable biological properties. Thus, the compounds of thepresent invention may be acylated, halogenated and oxidised.Hydrogenation gives Z-methylated steroids which, inter alia, may behydrolysed to 2a-methyl-3-oxo steroids of which some are known topossess valuable biological properties such, for example, as2a,17a-dimethyl-17B-hydroxyl-Su-andrOstan- 3-one.

The present invention provides new 3-enol ethers of2-hydroxymethyl-3-oxo-5oc-steroids including the Formula I below.

According to the present invention there is provided a process for thepreparation of 3-enol ethers of 2-hydroxy methyl-3-oxo-5a-steroidsincluding the formula where R has the same meaning as above.

it g

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A wide variety of reducing agents may be used for converting the2-formyl derivatives (II) which form the starting materials of theinvention, into the Z-hydroxymethyl derivatives (I) which form theproducts of the present invention. Such reducing agents, however, mustnot be acidic in character, nor must they be used in an acidic medium asthe resulting Z-hydroxymethyl derivatives (I) are very sensitive toacids which convert them into dimeric materials.

Conversion of 2-formyl derivatives (II) additionally substituted bysystems sensitive to both reduction and alkaline hydrolysis, such asCOCH OAc, is conveniently achieved catalytically employing Raney nickelas catalyst. Raney nickel as normally prepared is strongly alkaline inreaction. It is therefore advisable to free it from alkali before use,otherwise concomitant hydrolysis of the acylated ketol system may occur.This may be achieved by any method known to those skilled in the artsuch, for example, as treating it with ethyl acetate.

Platinum on charcoal in the presence of a sodium acetate buffer isanother valuable catalyst for hydro genation. Thus, for example, it maybe used to hydro genate catalytically the Z-formyl group in compoundssuch as2l-acetoxy-2-formyl-17a-hydroxy-3-methoxy-5upregn-2-ene-11,20-dione.

Organometallic hydrides such as, for example, lithium, sodium, magnesiumand calcium borohydrides, lithium aluminium hydride andtritertiarybutoxy aluminium hydride represent another group of reducingagents which are particularly valuable for reducing the 2-formyl groupin 17a-acyloxy-5a-pregnan-ZO-one derivatives. Lithium cyanoborohydridemay be valuable in certain instances.

The Ponndorf method of reduction may be employed for reducing 2-formylderivatives that do not contain additional carbonyl groups. Othermethods of reduction may be found in standard works of reference such asHouben-Weyl.

The 2-formyl derivatives (II) which form the starting materials of thepresent invention are prepared by the process of our copendingapplication No. 253,750, filed January 24, 1963. In this process, the3-enol ether of a 3-oxo-5a-steroid including the Formula III (where Rhas the meaning hereinabove defined) CD it? or a 3,3-dialkoxy-5a-steroidincluding the Formula IV AlkO (IV) is treated with the Vilsmeier reagent(see Houben-Weyl, Methoden der Organische Chemie, 4th ed., 1954, vol. 7(1), page 29 et seq.), preferably at approximately 0 C. and in a solventsuch as ethylenedichloride and the resulting iminium salt decomposedwith, for example, aqueous methanolic sodium acetate, when the 2-formylderivative (II) is obtained. As described in our copending application,the 2-formyl group may be intro duced into the 3-enol ethers of3-oxo-5a-steroids including 3-oxoandrostane, 19norandrostane,Sa-pregnane, oz, 19-norpregnane, cholestane, spirostane, ergostane,stigmastane and derivatives and analogues thereof which may beadditionally substituted by- Hydroxyl and acyloxy groups and functionalderivatives thereof in such positions as 5, 6, 11, 12, 15, 16 (including16-hydroxymethyl), 17, 18, 20 and 21 (including the condensationproducts of 16d,17lX-g1yCO1S with carbonyl components). Thiol groups atC are unaffected.

Carbonyl groups in such positions as 11, 12, 16, 17, 18 and 20.

Carbalkoxy groups at 13, 16, 17 or in the side chain.

Cyano groups at 13, 16 and 17.

Alkyl groups, in particular Me groups at 4, 5, 6, 11, 16, 17 and 21.

Alkenyl and alkynyl groups such as vinyl, allyl and propynyl at 17.

Methylene and ethylidene groups at 6, 11, 16, 16(17) and 17.

Lactone, ether and spiroketal residues: Spirolactone residues such asO.CO.CH .CH attached to C etheric groups at C and bridging C and Cspiroketal moieties such as are present in diosgenone.

Halogen groups and in particular chlorine and fluorine substituents inrings C and D or in the side-chain.

Unsaturated linkages at C C C C and C Ketol groups at 16-17, 17-20 and20-21 which are preferably acylated.

Corticoid side-chains, both acylated, or converted into such protected"derivatives as bismethylenedioxy, cyclic carbonates, acetonides ororthoformates.

Epoxides and halohydrins, particularly at C In reducing 2-formylderivatives containing the foregoing substituents, care should be takenby those skilled in the art in the choice of an appropriate reductant.

The process of the invention may be applied to the 3- enol ethers of2-formyl-3oxo-Swsteroids derived from the following steroids and 19-noranalogues thereof and acyl derivatives thereof as well asBismethylenedioxy derivatives, cyclic carbonates, acetonides andorthoformates of corticoids.

5a-androstane-3,17-dione and its 6- and 16-rnethyl derivatives, 6 andll-methylene derivatives and the 11- oxo-ll-hydroxyand 9(l1)-dehydroderivatives thereof.

17fi-hydroxy-5a-andrOstan-Bone and its 6-methyl derivatives and thell-oxo-ll-hydroxyand 9(11)-dehydro derivatives thereof.

17m alkyl-17fi-hydroxy-5m-androstan-3ones (wherein the alkyl groupcontains up to 4 carbon atoms) and its 6-methyl derivatives and the11-OXO-, ll-hydroxy and 9(11)-dehydro derivatives thereof.

17a alkyl 17fl-hydroxy-5a-androstan-3-ones (wherein the alkyl groupcontains up to 4 carbon atoms).

17a-alkynyl-17fl-hydroxy-5a-androstan-3ones (wherein the alkynyl groupcontains up to 5 carbon atoms).

5u-pregnane-3,20-dione and its 6 and 16-methyl derivatives and thell-oxo, ll-hydroxy and 9(11)-dehydro derivatives thereof.

17a-acetoxy-5a-pregnane-3,20-dione and the 6- and 16- methyl and16-methylene derivatives and the ll-oxo, 11- hydroxy and 9(11)-dehydroderivatives thereof.

17ix-acetoxy-21-fiuoro-5u-pregnane-3,20-dione and the 6 and 16-methyland 16-methylene derivatives and the 11- oxo, ll-hydroxy and9(1l)-dehydro derivatives thereof.

Sa-dihydro cortisone and hydrocortisone and the 6- methyl, 16-methyl,l6-methylene and l6a-hydroxy derivatives thereof.

16m,17a-isopropylidenedioxy-5e-pregnane 3,20 dione and the 6-methylderivative and the ll-oxo, ll-hydroxy and 9(l1)-dehydro derivativesthereof.

Sa-dihydro compound S and the 6-methyl, 16-methyl, 16-methylene,l6-hydroxy derivatives and the 9(l l)-clehydro derivatives thereof.

3-(3-0X0-17fi-hYdfOXY-5oc androst 17a yl) propionic pyridine.

acid and lactone and the ll-oxo, ll-hydroxy and 9(11)- dehydroderivatives thereof.

5a-dihydrotestololactone.

3-oxo-5a-pregn-l7-enoic acid (esters) and the 6-methyl derivative andthe ll-oxo, ll-hydroxyand 9(ll)-dehydro derivatives thereof.

It will be seen that the 3-enol ethers of the2-hydroxym6thY1-3-OXO-5oc-St61'0ld5 derived from the compounds namedabove, comprise compounds of the general formula:

O.CO.CH .CH

R is hydrogen, methyl, methylene or hydroxyl R and R together may be Ris hydrogen or methyl, and B is a single bond When R is 0x0 or hydroxyand is either a single or double bond when R is hydrogen.

Following is a description by way of example of methods of carrying theinvention into effect.

EXAMPLE 1 l 7,8-A cetoxy-Z-Hydroxymethyl-3-Mefl10xy- 5 oc-A ndrost-Z-Enenoon H Alcoa, H

A solution of 17/3-acetoXy-2-formyl-3methoxy-h-androst-2-ene (l g.) inmethanol (25 ml.) was treated with sodium borohydride (0.2 g.) for 15minutes at room temperature. Addition of water gave a solid which wascrystallised from aqueous methanol containing a trace of 17p-acet0xy 2hydroxymethyl-3rnethoxy-Saandrost-Z-ene separated in needles, M.P. -122C., [ab -{41 (c., 0.98 in dioxan).

EXAMPLE 2 '---Me Me mom- EXAMPLE 317a-Acetoxy-Z-Hydroxymethyl-3-Meth0xy-5a- Pregn-Z-En-ZO-One COMe ' --OAcMe i Boom-l i MeO- I l H 170: acetoxy 2 formyl 3 methoxy 5oz pregn 2-en-20-one (2 g.) was added to a stirred suspension of lithiumborohydride (0.3 g.) in anhydrous tetrahydrofuran (40 ml.). The mixturewas stirred for 5 minutes, poured into water, and the product isolatedwith ether. crystallisation from aqueous methanol containing a trace ofpyridine gave17a-acetoxy-2-hydroxymethyl-3-methoxy-Sa-pregn-Z-en-ZO-one,

my 3400, 1724 and 1700 cm? EXAMPLE 4 21 -Acet0xy-17ot-Hydr0xy-2-Hydr0xymethyl-3- M eth0xy-5 a-Pregn-Z-Ene-I 1 ,ZO-DionecrnoAc 60 ---OH f Me Hocrr,-'

MeOL/ 1'1 tion, the filtrate concentrated, water was added and theproduct isolated with dichloromethane. It was purified from aqueousethanol containing a trace of pyridine to give2l-acetoxy-17a-hydroxy-2-hydroxymethyl-3-methox 5 a-pregn-Z-ene-I1,20-dione,

EXAMPLE 5 1 7fi-A cetoxy-Z-Hydroxymethyl-3-Meth0xy-19- A solution of17fi-acetoxy-2-formyl-3-methoxy-19-nor- Sa-androSt-Z-ene (1 g.) in drytetrahydrofuran (10 ml.) was added to lithium borohydride (200 mg.) indry tetrahydrofuran (10 ml.) at room temperature and the mixture stirredfor 10 minutes. Thereafter, water was added and the product isolatedwith ether. Purification by crystallisation gave17fl-acetoxy-2-hydroxymethyl-3-rnethoxyl9-nor-5a-androst-2-ene.

EXAMPLE 6 1 7p-H droxy-2-H droxymethyl-3-Methoxy-1 7 u-Methyl-19-N0r-5a-Androst-Z-Ene A solution of acetoxy 2 formyl 17ozmethyl 3 methoxy 19 nor 5oz androst 2 ene (1 g.) in dry tetrahydrofuran(25 ml.) was treated with lithium aluminuium hydride (0.75 g.) and themixture stirred under reflux for 1 /2 hours. The mixture was cooled,treated with water, and the product isolated with ether. Crystallizationgave 173 hydroxy 2 hydroxymethyl 3 methoxy 17a methyl 19 nor 5a androst2 ene,

li? 3400 and 1697 cm.-

We claim:

1. A process for the preparation of a 2(3) unsaturated 3-enol ether of a2-hydroxymethyl-3-oxo-5a-steroid selected from the group consisting ofthe androstane, 19- norandrostane, pregnane, 19-norpregnane, cholestane,spirostane, ergostane and stigmastane series, which process comprisesreducing a corresponding 3-enol ether of a 2-formyl-3-oxo-5a-ster0idwith a reducing agent comprising a source of hydrogen in a solventmedium under non-acid conditions.

2. A process as claimed in claim 1 wherein the reducing agent is a metalborohydride.

3. A process as claimed in claim 1 wherein the reducing agent is lithiumaluminium hydride.

4. A process as claimed in claim 1 wherein the reduction is effected bycatalytic hydrogenation employing platinum on charcoal in the presenceof a sodium acetate buifer.

5. A 3-enol ether of the formula:

wherein R is O-lower alkyl;

R is selected from the group consisting of hydrogen and methyl R isselected from the group consisting of hydrogen,

x0 and hydroxy;

R is selected from the group consisting of hydroxy,

-COCH COCH F, COCH OH and -COCH O(acety1);

R is selected from the group consisting of hydrogen, lower alkyl, andlower alkynyl when R is hydroxy and is selected from the groupconsisting of hydrogen, hydroxy and acetoxy when R is selected from thegroup consisting of COCH COCH F, COCH OH and COCH O(acetyl);

R and R when taken together are selected from the group consisting of0x0 and R is selected from the group consisting of hydrogen,

methyl, methylene and hydroxyl;

R is selected from the group consisting of hydrogen and methyl, and

B is a single bond when R is oxo and hydroxy and is selected from thegroup consisting of single and double bonds when R is hydrogen.

6. 17,5 acetoxy 2 hydroxymethyl 3 methoxy 5 a-androst-2-ene.

7. 17,3 hydroxy 2 hydroxymethyl 3 methoxy 17a-methyl-Son-androst-Z-ene.

8. 17a acetoxy 2 hydroxymethyl 3 methoxy 5a-pregn-2-en-20-one.

9. 21 acetoxy 17a hydroxy 2 hydroxymethyl3-methoxy-5a-pregn-2-ene-11,20-dione.

10. 17B acetoxy 2 hydroxymethyl 3 methoxy 19-nor-5 a-andrOst-Z-ene.

17x-n1ethyl-19-nor-5a-androst-2-ene.

No references cited.

5. A 3-ENOL ETHER OF THE FORMULA: